The function of tumor suppressor genes is a major focus of recent attempts to develop innovative therapeutics for the treatment cancer. The products of tumor suppressor gene expression are generally characterized as negative regulators of cell proliferation (Knudson, A. G. (1993), Weinberg, R. A. (1995)). Thus, therapeutic approaches to date include gene therapies to restore inactive or missing tumor suppressor function in cancer cells to re-establish normal cellular function or induce apoptosis (Clayman, G. L. (2000), Knudson, A. G. (1993)).
Functional loss of tumor suppressor genes also has been linked to hyperproliferative inflammatory or autoimmune diseases that have cellular hyperproliferation as one of their characteristics (Cordan-Cardo, C. and Prives, C. (1999)) and/or defective apoptosis (programmed cell death) (Mountz, J. D. et al. (1994)). These include: rheumatoid arthritis, systemic lupus erythmatosus, psoriatic arthritis, reactive arthritis, Crohn's disease, ulcerative colitis and scleroderma. Table 1 lists literature examples which suggest that such a link may exist.
TABLE 1Literature Examples Suggesting that Biological Expression of TP53Tumor Suppressor Mutation/Inactivation Relates to NoncancerHyperproliferative Disease, Autoimmune Disease and Inflammation.ImpactDisease EffectReferenceIncreased IL6ProliferationHan et al. (1999)InflammationRheumatoid ArthritisIncreased metalloproteinasesTissue DegradationSun, Y. et al. (2000)Increased proliferation ofRheumatoid arthritisAupperle, K. R. et al.synovial cells(1998)Genetic instabilityChronic inflammationTak. P. P. et al. (2000)and disease progressionUlcerative colitisLang, S. M. et al.(1999)Increased expression ofProliferationBanerjee, D. et al.E2F regulated genesDrug resistance(1998)(TS, DHFR)Multiple autoimmuneand inflammatory diseasesViral proteins expressionAthersclerosisTanaka, K. et al.leading to p53 inactivation(1999)Increased angiogensisSupports hyper-proliferativeZhang, L. et al. (2000)States, ex. enablingatheromaorpannus formation.
Loss of RB/p16 function can result in similar proinflammatory, proliferative and dedifferentiating effects on cells (Carson, R. A. and Haneji, N. (1999); Shim, J. et al. (2000); Wolff, B. and Naumann, M. (1999); DiCiommo et al. (2000)), and alteration in cell-cell interactions (Plath et al. (2000)). Inactivation of tumor suppressor function by somatic mutation or via interaction with virally-encoded proteins is proposed to contribute to the proliferative/inflammatory aspect of athersclerosis, restenosis or other hyperproliferative diseases (Tanaka, K. et al. (1999); Aoki, M. et al. (1999); Guevara, N. V. et al. (1999); Iglesias, M. et al. (1998)). Finally, the expression of the proinflammatory cytokine, macrophage inhibitory factor (MIF), may be capable of inactivating p53 function in some cell types (Hudson, J. D. et al. (1999); Cordon-Cardo, C. and Prives, C. (1999); Portwine, C. (2000)).